Recent scans on SNP-by-smoking on pulmonary phenotypes
| Ref. | Study | N | Outcome | Test | p < 5e-08 |
|---|---|---|---|---|---|
| (Hancock et al. 2012) | Meta (19) | 50K | FEV1 |
joint (Aschard et al. 2011) | nearby 3 genes |
| (Wain et al. 2015) | UKBiobank | 50K | FEV1/FEV1-FVC |
interaction | – |
Recent proposals to improve power by aggregating variants
The COPD-related outcomes are appropriate for the 2nd approach, as the proportion of African ancestry was shown to be associated with the risk of COPD (Kumar et al. 2010)
(Renier et al. 2017)
(Aschard et al. 2015)
FEV1/FEV1pp, FVC/FVCpp, FEV1_FVC, pctEmph_Slicer, TLCpp, finalGoldSmokCigNow, CigPerDayNow > 15, CompletedSchool > 237K long (>10kb) local ancestry segments (Parker et al. 2014)
Confounding factors other that global ancestry \(a_g\):
FEV1 ~ Age + Age^2 + Gender + Height + PackYears + SmokCigNowpctEmph_Slicer traitThis (marginal) model was used in (Parker et al. 2014).
Is it OK for interaction?
SmokCigNow + ATS_PackYears → Duration_Smoking + log_CigPerDaySmokAvg + SmokCigNow + SmokCigNow0_15 + SmokCigarNowMore details in our previous talk COPDGene African-Americans & QQ plots
SmokCigNow (7 traits)\(z = [z_1; z_2; \dots]^T \sim N(0, \Sigma)\)
under the null hypothesis
2.5Bonferroni 0.05 / 37K = 1.4e-06
| Trait | Exposure | z-score | p-value |
|---|---|---|---|
| FEV1pp | SmokCigNow | 4.5 | 7.3e-06 |
| Omnibus | SmokCigNow | – | 5.7e-05 |
| FEV1_FVC | SmokCigNow | 3.9 | 1.1e-04 |
| FEV1 | SmokCigNow | 3.8 | 1.4e-04 |
| Trait | Exposure | z-score | p-value |
|---|---|---|---|
| FEV1 | SmokCigNow0_15 | 4.2 | 2.6e-05 |
| FEV1pp | SmokCigNow0_15 | 4.1 | 4.9e-05 |
| FVC | SmokCigNow0_15 | 4.0 | 6.9e-05 |
| Omnibus | SmokCigNow_15 | – | 1.5e-04 |
| FVCpp | SmokCigNow0_15 | 3.7 | 2.5e-04 |
| Data | Min size | Mean size |
|---|---|---|
| Local ancestry | 10,000 bp | 13,000 bp |
| ENCODE tissue-specific | – | 150 bp |
| Intersection | 10,000 bp | 11,000 bp |
We observed top associated genes have been published to be associated with epigenetic changes.
Hypothesis: the mechanism of ancestry-based association is:
Smoking → Up/Down Methylation → COPD-related phenotype
Wan et al., Smoking-associated site-specific differential methylation in buccal mucosa in the COPDGene study (2015)
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———. 2015. “Leveraging local ancestry to detect gene-gene interactions in genome-wide data.” BMC Genetics 16 (1). BMC Genetics: 124. doi:10.1186/s12863-015-0283-z.
———. 2017. “Evidence for large-scale gene-by-smoking interaction effects on pulmonary function.” International Journal of Epidemiology 46 (3): 894–904. doi:10.1093/ije/dyw318.
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